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Identification of cytochrome P450 isoenzymes involved in metabolism of (+)-praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupled with tandem mass spectrometry
Jing W.-H.1; Song Y.-L.1; Yan R.1; Wang Y.-T.1,2
2013
Source PublicationJournal of Pharmaceutical and Biomedical Analysis
Volume77Pages:175
Abstract

Angular-type pyranocoumarins (APs) show attractive prospects in anti-hypertension, chemotherapy and anti-HIV treatment. Previous studies revealed extensive hepatic metabolisms of several APs following similar pathways. This study investigated the enzyme kinetics and the main CYP450 isozyme(s) involved in metabolism of (+)-praeruptorin A (dPA), an AP with significant cardio-protective activities, in human liver microsomes (HLMs) using ultra high-performance liquid chromatography coupled with a hybrid quadrupole-linear ion trap mass spectrometry (UHPLC-QT-MS/MS). dPA produced 6 metabolites via hydrolysis (M1-M3), oxidation (M4-M6), and hydrolysis followed by acyl migration (M2 or M3). Oxidation at the C-3' side chain instead of the coumarin ring was consolidated with the aromatic proton signal in NMR spectra. The major metabolite (-)-cis-khellactone (M1) followed biphasic kinetics in HLMs with high affinity (Km1 0.02μM) and intrinsic clearance (CLint1, invitro1.29mL/min/mg protein), whereas other metabolites (M2-M6) fitted typical Michaelis-Menten kinetics with lower affinity (Km 3.85-39.13μM). Recombinant human CYP3A4 showed the highest activity toward M1 and M4 formation, while it was CYP2C19 for M2/M3 and M5 and CYP2B6 for M6. Principal component analysis of the metabolite formation profile of dPA also revealed the highest similarity between CYP3A4 and HLMs. Both quercetin (CYP2C8 inhibitor) and ketoconazole (CYP3A4 inhibitor) showed 60-100% inhibition of M1-M4 and M6 formations in HLMs, while M5 formation was mainly inhibited by α-naphthoflavone (CYP1A2 inhibitor, 70-80%) and quercetin (90%). Moreover, formations of all metabolites were predominantly inhibited by CYP3A4 antibody (37-68%). These findings shed a light on main involvement of CYP3A4 in human hepatic elimination of APs, indicating potential drug interactions. © 2013 Elsevier B.V.

Keyword(+)-praeruptorin a Angular-type Pyranocoumarins Cyp 3a4 Human Liver Microsomes Uhplc-qt-ms/ms
DOI10.1016/j.jpba.2013.01.023
URLView the original
Language英语
The Source to ArticleScopus
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被引频次[WOS]:14   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题Institute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
2.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
First Author AffilicationInstitute of Chinese Medical Sciences
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Jing W.-H.,Song Y.-L.,Yan R.,et al. Identification of cytochrome P450 isoenzymes involved in metabolism of (+)-praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupled with tandem mass spectrometry[J]. Journal of Pharmaceutical and Biomedical Analysis,2013,77:175.
APA Jing W.-H.,Song Y.-L.,Yan R.,&Wang Y.-T..(2013).Identification of cytochrome P450 isoenzymes involved in metabolism of (+)-praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupled with tandem mass spectrometry.Journal of Pharmaceutical and Biomedical Analysis,77,175.
MLA Jing W.-H.,et al."Identification of cytochrome P450 isoenzymes involved in metabolism of (+)-praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupled with tandem mass spectrometry".Journal of Pharmaceutical and Biomedical Analysis 77(2013):175.
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